Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) exhibit a poor prognosis with 5-year overall survival rates around 15%, all stages combined. Most of these primary liver malignancies are metastatic at diagnostic, with only limited therapeutic options, relying mainly on systemic therapies. Treatment modalities are different yet partially overlapping between HCC and BTC. The complex molecular profile of BTC yields to several actionable therapeutic targets, contrary to HCC that remains the field of antiangiogenic drugs in non-molecularly selected patients. Immunotherapy is now validated in the first line in HCC in combination with bevacizumab, while clinical activity of single agent immunotherapy appears limited to a subset of patients in BTC, still poorly characterized, and combinations are currently under investigation. In this review, we provide a critical evaluation and grading of clinical relevance on (i) the main prognostic biomarkers in HCC and BTC, (ii) the main theragnostic biomarkers in both tumors, and lastly (iii) what is recommended in clinical practice.

Main prognostic factors of anal squamous cell carcinoma (ASCC) are tumor size, differentiation, lymph node involvement, and male gender. However, they are insufficient to predict relapses after exclusive radiotherapy (RT) or chemoradiotherapy (CRT). Fusobacterium nucleatum has been associated with poor prognosis in several digestive cancers. In this study, we assessed the association between intratumoral F. nucleatum load and clinico-pathological features, relapse, and survival in patients with ASCC who underwent abdominoperineal resection (APR) after RT/CRT. We retrospectively analyzed surgical samples from a cohort of 166 patients with ASCC who underwent APR. F. nucleatum 16S rRNA gene sequences were quantified using real-time quantitative PCR. We associated F. nucleatum load with classical clinicopathological features, overall survival (OS), disease-free survival (DFS), and metastasis-free survival (MFS) using Cox regression univariate and multivariate analyses. Tumors harboring high loads of F. nucleatum (highest tercile) showed longer OS and DFS (median: not reached vs. 50.1 months, p = 0.01, and median: not reached vs. 18.3 months, p = 0.007, respectively). High F. nucleatum load was a predictor of longer OS (HR = 0.55, p = 0.04) and DFS (HR = 0.50, p = 0.02) in multivariate analysis. High F. nucleatum load is an independent favorable prognostic factor in patients with ASCC who underwent APR.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, with significant public health concerns. This review examines the landscape of KRAS inhibition in colorectal cancer (CRC), focusing on recent advances in therapeutic strategies targeting this oncogene. Historically deemed undruggable due to its complex structure and essential role in tumorigenesis, KRAS mutations are prevalent in CRC and are associated with poor prognosis. However, breakthroughs in drug development have led to the emergence of KRAS inhibitors as promising treatment options. This review discusses various classes of KRAS inhibitors, including covalent and non-covalent inhibitors, as well as combination therapies aimed at enhancing efficacy and overcoming resistance mechanisms. It highlights recent clinical trials evaluating the efficacy of KRAS inhibitors either as monotherapy or in combination with other agents, such as anti-EGFR antibodies. Despite challenges such as resistance mechanisms and tumor heterogeneity, the development of KRAS inhibitors represents a significant advance in CRC treatment and holds promise for improving patient outcomes in the future.

Primary mediastinal germ-cell tumors (PMGCTs) account for 1%-3% of all germ-cell tumors (GCTs). Non-seminoma have a poorer prognosis compared to their gonadal counterpart and, according to the International Germ Cell Cancer Collaborative Group, they are considered 'poor risk' disease. Medical treatment is the same, with overall survival (OS) being ∼40%, declining to 10%-15% at 3 years in case of lung and non-visceral metastases. Patients failing first-line chemotherapy have a dismal prognosis, with only 5%-10% of cases being cured in the salvage setting. High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been successfully used to treat patients with relapsed or refractory gonadal GCTs. This retrospective study aimed to investigate the value of HDC with ASCT in the whole population and define primary mediastinal non seminoma germ cell tumor (PMNSGCT) patient subgroups, who were registered in the European Society for Blood and Marrow Transplantation database from January 2000 to January 2018. Sixty-nine adult male patients with PMNSGCT were included. HDC consisted mainly of carboplatin/etoposide doublet, and most patients received HDC as part of a multiple sequential HDC program. OS was 43.3% at 2 years, and 34.7% at 5 and 10 years for the entire cohort. Analysis of outcomes showed that patients undergoing HDC as upfront therapy had a better progression-free survival (PFS) and OS compared to those treated in subsequent relapses (5-year PFS 51.8% versus 26.8% and 5-year OS 51.3% versus 25.9%). Better remission status before transplantation was predictive of the benefit of HDC. Three treatment-related deaths were recorded. To our knowledge, this is the most extensive retrospective study of HDC in PMNSGCTs patients and the first to thoroughly investigate potential predictors of benefit from this treatment. HDC with ASCT may well represent a therapeutic option in patients with PMNSGCTs after the first relapse or even as a front-line program.

Selective internal radiation therapy (SIRT) is a promising option for liver-only unresectable intrahepatic cholangiocarcinoma (iCCA). The Real-SIRTCCA study retrospectively assessed the benefit of adding SIRT to chemotherapy in this setting within the French nationwide observational cohort ACABi-GERCOR-PRONOBIL. Inclusion criteria were advanced iCCA with limited or no extrahepatic disease, treated with first-line gemcitabine plus platinum chemotherapy +/- concurrent SIRT. All patients treated with chemotherapy and concurrent SIRT were included. To ensure groups’ similarity, a rigorous selection was applied to the chemo-only group, with exclusion of patients with liver involvement >50% and extrahepatic metastases. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), objective response rate (ORR) and tumor resection rate. Propensity score and inverse probability of treatment weighting (IPTW) propensity approaches were used to address confounding factors between groups. Between July 2007 and December 2023, 277 patients met the Real-SIRTCCA inclusion criteria, with 88 in the chemo-SIRT group and 189 in chemo-only group. Chemo-SIRT was associated with longer PFS (median = 10.8 vs. 5.5 months, hazard ratio [HR] 0.54, 95% CI 0.41-0.71, p <0.0001), a trend for longer OS (median = 22.5 vs. 15.1 months, HR 0.76, 95% CI 0.57-1.01), higher ORR (58.3% vs. 28.5%, odds ratio [OR] 3.51, 95% CI 2.03-6.09, p <0.0001), and resection rate (18.7% vs. 8.8%, p = 0.0279) compared to chemo-alone. After IPTW, the superiority of chemo-SIRT was confirmed with better PFS (HR 0.55, 95% CI 0.45-0.66, p <0,0001), OS (HR 0.70, 95% CI 0.58-0.85, p = 0.0004), ORR (OR 3.17, 95% CI 2.18-4.49, p <0.0001) and resection rate (OR 2.94, 95% CI 1.71-5.03, p <0.0001). Adding SIRT to first-line chemotherapy significantly improved survival outcomes, ORR, and secondary tumor resection rates in locally advanced iCCA. Prospective randomized data are needed to confirm these results. Herein, we report the results of the Real-SIRTCCA study, comparing the efficacy of the gemcitabine-platinum systemic first-line chemotherapy with or without selective internal radiation therapy (SIRT) in 277 patients with locally advanced intrahepatic cholangiocarcinoma within the cohort ACABi-PRONOBIL. An improvement of progression-free survival, overall survival, tumor response and secondary surgical resection rate was observed in favor of chemo-SIRT, before adjustment and after inverse probability of treatment weighting propensity score analyses. Even though prospective randomized data would be needed to confirm these findings, we believe that this study constitutes new evidence of the potential benefit of combining SIRT with chemotherapy. The safety and efficacy of this strategy whether as a bridge to intent-to-cure strategies or in a palliative setting, should encourage its adoption in a larger panel of clinical centers, or at very least, prompt clinicians to refer their patients to centers where SIRT is performed. NCT04935853.